The Baltimore Longitudinal Study of Aging (BLSA), the Intramural NIA's current major research program on human aging, has been conducted at the Gerontology Research Center since 1958, and is now active at the NIA-ASTRA (Translational Research on Aging) Unit located at Harbor Hospital (Baltimore). The study continues to represent a consortium of scientists who work to characterize normal and pathological aging. The team of researchers currently managing the study is implementing major changes in its design and assessment technology. The primary scientific goals remain those that were reported in the original BLSA legacy: 1) to identify age-associated differences among individuals which are not explained by diseases, and 2) to characterize factors that affect the transitions from normal to pathological aging. However, new measures are being implemented that are aimed at gaining a better understanding of the effect of age and diseases on the process that leads to mobility disability and poor quality of life in many older adults. The focus is on an integrative and multidisciplinary approach, and the compensatory mechanisms that, naturally implemented at multiple levels (cells, tissues, organs, whole body, society) allow many older persons to maintain a high level of mobility, in spite of multiple pathological process. The study population is a cohort of volunteers that are followed for life over multiple follow-up visits. Many of the active participants have been in the study for more than 20 years, and some for as long as 44 years. The study is currently enrolling individuals 70 years and older who extremely functional and have exceptional health. This new aspect of the BLSA has been name "the study of IDEAL (Insight into the Determinants of Exceptional Aging and Longevity). In the past, the BLSA has been the gold-standard reference for all epidemiological studies on aging. Important findings in the area of cardiovascular research, factors affecting the risk of prostate cancer, age-associated decline of cognitive function, glucose metabolism, muscle strength and bone strength were published even in recent years. Moving the BLSA to the ASTRA unit was vital to implementing some of the new knowledge in a clinical perspective. This goal will be pursued by conducting, in parallel, the BLSA ancillary studies that, being limited to a small number of participants and adressing a single, pre-formulated hypothesis, are more likely to provide information that can be directly applied in clinical medicine. The structure of the new BLSA design is based on three levels of measures: 1. The reference out come measures are physical and cognitive function and all other measures, directly or indirectly, are aimed at understanding the mechanisms by which old age is associated with high risk of developing mobility disability and impaired cognitive function. Accordingly, the BLSA collects an extensive set of measures of many difference aspects of physical and cognitive function; 2. The intermediate level includes measures of anatomical integrity and functionality of the physiological systems that are important for mobility: central nervous system, peripheral nervous system, muscle, bone and joints, delivery of substances important for energy production, sensory systems that provide feedback from the environment; 3. The third level includes the physiological systems that are important to maintain a stable biological homeostasis and include measures for immune function, hormones, oxidative stress/antioxidants, autonomic nervous system, nutritional intake, and physical activity. The hypothesis of the study is that a dysfunction of the systems that maintain the biological homeostasis is the primary cause of the age associated decline of physical function and of the development of frailty. In essence this specific aim will be pursued by two sub-projects, which are somewhat different in the design of practical aspects by highly related and complementary in the scientific scope. Considerable resource have dedicated to restructure, document and clean the data that were collected over the last 50 years. This project is already in an advanced stage of development and is already producing important results, concerning clinical feature for the diagnosis of prostate cancer associated with negative prognosis, secular trend of WBC and its relationship with the decline of mortality over the last half of the century, genetic traits that are associated with accelerated decline of physical function. An essential part of this plan is the inventory, classification and quality control of the entire collection of the biological specimens (urines, blood, serum, plasma, red blood cells etc) collected in BLSA participants during the entire course of the study. In addition, we plan to perform a wide genome scan (Illumina 550K) in around 1450 participants who have available DNA. For the DNA QC, 14 highly informative loci were typed in all DNA samples on storage, in order to obtain a unique identifier, and the "signature" was compared across different samples collected at multiple points in time. In this way we have minimized possible misclassification errors that can occur by mislabeling or mistaken archival or biological samples. Using the rich collection of phenotypes collected over many years and the Illumina genotypes, the BLSA has contributed data to many genetic consortia looking at the contribution of genetic variability to different human phenotypes, such as blood pressure, circulating lipids, uric acid, pro-inflammatory markers and many others. In addition, we are starting new work on gene-environment interaction. An important sub-project consists in recruiting a new cohort of exceptionally healthy older persons (IDEAL), look at the cross-sectional characteristics of this group compared to the general population, and measure a number of physiological parameters that may be directly or indirecly connected with physical and cognitive function. From this prospective, the future of the BLSA is to become a permanent laboratory of physiology that study the different physiological changes that occur over the aging process, with the final aim of understanding their inter-relationships and describing the mechanisms by which they contribute to the maintainability of the homeostatic equilibrium. The details of this project, that will be started in 2009, reported in a dedicated section of this report. Since many BLSA participants who become sick and disabled were often unable to come to the Baltimore clinic for a traditional visit in the clinic creating a severe ascertainment bias informative censoring) in the study of age-related outcome the BLSA has started a "home visit" project aimed at collecting information from individuals that are no longer able to come to the Baltimore Clinic for their traditional visit. This portion of the project is handled through a R&D contract mechanism is also detailed in a special section of this report and that is very successful.